In comparison to other imaging modalities such as computerized tomography and nuclear medicine techniques, quantitative functional magnetic resonance imaging (MRI) of the human lung is relatively poorly developed. These MRI techniques are not limited by exposure to ionizing radiation or contrast injection and thus open the door to unlimited repeated studies, and offer the possibility of new fields such as temporal imaging. The long-term objective of this program is to develop and establish quantitative functional proton MRI in the human lung as a readily available means of providing regional information on perfusion, ventilation and gas exchange that is physiologically and clinically relevant. Techniques we have developed allow us to quantitatively measure the spatial distributions of lung density (a direct measure of air content), pulmonary blood flow, and specific ventilation. Together these techniques permit us to quantitatively map ventilation- perfusion ratio (V? A/Q?), which uniquely determines pulmonary gas exchange, with a spatial resolution that is close to the scale of the functional gas exchange unit of the human lung. The overall goal of the first five years of this Bioengineering Research Partnership (BRP) is to make these research techniques translatable to the wider research community so that they may be used as biomarkers in research studies and in clinical trials, with a future goal of clinical applicability To do so, these techniques need to: a) have their physiological interpretation strengthened to provide a rigorous basis for interpretation of the results they produce; b) be further developed into efficient and accessible techniques for clinical studies; and c) be subjected to validation studies to prove their applicability for clinical studies. To these ends we propose a coordinated series of studies that will: 1) use highly anatomically-realistic in-silico modeling to place the physiological interpretation of all imaging modalities on a sound footing; 2) validate imaging of perfusion, ventilation and V A/Q by comparing with injected and inhaled microsphere measurements in a pre-clinical large animal model; 3) cross- validate imaging of V A/Q in humans with quantitative measures of VA/Q obtained from the gold-standard non-imaging approach of the multiple inert gas elimination technique, both in the normal and diseased lung; and 4) optimize the current MR methodology and expand the repertoire of functional lung imaging with improved techniques. Completion of this BRP will result in deliverables of an accessible suite of validated quantitative functional MR lung imaging methods for use on commercially available scanners to measure density, perfusion, ventilation, and ventilation-perfusion ratio.